Although a lung is a portal of entry for this M. tuberculosis and chronic pneumonia is the most common disease caused by M. tuberculosis infection, the specific nature of the pulmonary host response to this pathogen is relatively unknown. The central goal of the studies outlined in this proposal is to determine whether components of the early pulmonary immune response are critical determinants for resistance or susceptibility to disease caused by M. tuberculosis. The specific aims will address the role of TNF-alpha, beta chemokines and the B7/CD28/CTLA4 costimulation pathway in the initiation and amplification of the pulmonary host response to aerosol infection with M. tuberculosis. Preliminary studies using transgenic mice with a local inhibition of TNF-alpha in the lung (SPCTNFRIIFc mice) indicate that blockade of TNF-alpha selectively in the lung results in early deaths, severe lung pathology and an alteration of antigen specific immunity. These studies also indicate that transgenic mice with local inhibition of the immune response in the lung are a useful model to study pulmonary host defense. Further studies are proposed to compare the response that develops in the lung vs. regional lymph nodes in wildtype and SPCTNFRIIFc mice. To investigate the role of beta chemokines in the pulmonary host defense, transgenic mice that secrete a virally encoded inhibitor of all chemokines has been generated. The phenotype of these mice will be determined then used to investigate the role of beta chemokines in the initiation of the pulmonary host response to M. tuberculosis. To investigate the role of the B7/CD28/CTLA4 costimulation pathway in the initiation and amplification of the pulmonary host response to M. tuberculosis, transgenic mice that secrete an inhibitor of the B7/CD28/CTLA4 co stimulation pathway will be generated, characterized then used in experiments examining the immune response to M. tuberculosis. To determine the relative importance of the intrapulmonary component of the immune response vs the systemic immune response, in each of the project specific aims, mice will be included with both local inhibition of the immune response and systemic inhibition. In the studies examining the pulmonary host response to M. tuberculosis, infections will occur via the aerosol route because inhalation is the usual route of infection in humans. The primary endpoints will include bacterial burden, lung histology, survival and the phenotypic and functional characteristics of the immune response. The proposed studies should advance the existing knowledge of the specific nature of the pulmonary immune response to M. tuberculosis, will directly test the role of these mediators in host defense against M. tuberculosis, suggest important targets for novel therapies and elucidate role of specific mediators of the host immune response that are critical for the induction of an antigen specific immune response by candidate vaccines.